Fetal exposure to maternal Major Depressive Disorder (MDD) during pregnancy is consistently associated with newborn medical and neurobehavioral deficits and long-term emotional, behavioral, and social problems in the child. Treatment of prenatal MDD is critical. Selective serotonin reuptake inhibitors (SSRIs) and dual-action serotonin and norepinephrine reuptake inhibitors (SNRIs) are the pharmacological treatment of choice for MDD (collectively SRIs), and are used by an estimated 37% of depressed pregnant women. Both prenatal MDD and SRI exposure alter the placenta and intrauterine environment and pose risks to developmental outcomes. This creates a significant dilemma for pregnant women and their health care providers when making choices about treatment for MDD. Prenatal SRI exposure contributes to altered serotonin availability in the developing fetus. Serotonin is a key regulator of ultradian sleep-state alternations and circadian sleep-wake rhythms; SRIs alter serotonin availability and these processes. Animal studies show that early SRI exposure alters fetal sleep state development and leads to permanent negative consequences later in development. Early sleep state patterns predict abnormal neurodevelopment and child behavior problems. Therefore, alterations in sleep processes are not only a potential outcome related to prenatal exposure, but may also be a potential mechanism for other long term effects. However, to date, there are no prospective, long term studies on human infant sleep following prenatal SRI exposure. We are currently conducting a NIMH funded (R01) study to determine the effects of prenatal SRI and MDD exposure on the fetus and newborn through 30 days of age, with systematic measures of sleep state and neurobehavior in the fetus and infant through the first month of life. In the current proposal we plan to assess at least 153 of the infants from the prenatal study cohort when they are 18-20 months of age to examine the longer term effects from early SRI or MDD exposure on sleep-state organization, 24-hour sleep-wake rhythms, and diurnal urinary excretion of melatonin sulfate, cortisol, epinephrine, and norepinephrine. Variables that may influence outcomes will be measured, including postpartum maternal mood, anxiety, stress, breastfeeding status, and environmental variables. The primary aim is to determine if prenatal SRI exposure alters infant sleep state organization, circadian rhythms, and neurobehavioral development at 18 months of age. This includes determining if the outcomes are altered if maternal MDD is remitted during the pregnancy and postpartum. Exploratory aims include determining if the magnitude and diurnal pattern of urinary excretion of melatonin sulfate, cortisol, norepinephrine, and epinephrine excretion is altered in SRI or MDD exposed infants and whether urinary melatonin sulfate excretion is associated with ultradian and circadian patterns, externalizing behaviors, and activity level in infants. PUBLIC HEALTH RELEVANCE: Prenatal exposure to antidepressant medications is related to adverse outcomes in infants and animal studies show that long term outcomes may include changes in sleep, circadian rhythms, mood and behavior. We plan to study the effects of prenatal antidepressant exposure on sleep and biological rhythms in children 18-20 months of age who were previously enrolled in a prenatal to newborn study. The information from this study, combined with the prenatal study data, will lead to better guidelines for the treatment of depression during pregnancy.